Project Summary/Abstract The goal of this proposal is to develop a novel approach for tumor cells ablation, while leaving healthy cells alive. This approach is based on 123I, a radioactive iodine isotope that emits Auger electrons. Auger electrons have the advantage of dissipating their energy in a very narrow radius, principally confined to only 10 nanometers. Therefore, unlike the more commonly used ?- and ?-emitters, Auger electron emitters inflict cellular DNA damage only at their targeted site, while leaving healthy cells in the immediate vicinity unaffected. We intend to target the DNA of cancer cells by conjugating 123I to inhibitors of the DNA repair enzyme PARP1. In preliminary experiments, we have shown these agents can efficiently transport ionizing radiation into the nuclei of cancer cells, and we have demonstrated that they are particularly useful for the delivery of targeted payloads to brain tumors. This use relies on the expression of PARP1 in brain tumors being far higher than in the healthy surrounding brain tissue. In addition, Auger emitting PARP1 radiopharmaceuticals are also less likely to damage kidney and liver than ?- or ?-emitting radionuclides, because in those organs, the overwhelming amount of activity should be retained outside of the nucleus, where the toxicity of Auger emitters is significantly lower. The Specific Aims of this proposal are to synthesize a library of radioiodinated PARP1 targeted inhibitors, and to determine which of them will most likely be successful as Auger 123I-labeled radiotherapeutics, based on their bioavailability, metabolic stability, tissue concentrations and residence times. Parallel SPECT imaging experiments will be used to study the whole body biodistribution and cellular PARP1 expression before and after DNA damaging treatment. For the 123I-labeled lead compound, we will determine extensive pharmacodynamic data, both in vitro as well as in vivo. We will perform a dose escalation study, and measure the effects on tumor growth and systemic toxicity. Infiltrative mouse models will be used to determine the potential impact of this novel radiotherapeutic drug. We will further design combination treatment studies with PARP1 Auger emitters, where sub-therapeutic doses of external beam radiation are used to increase activity and DNA proximity of PARP1, and therapeutic doses are used to increase overall PARP1 expression, with both effects increasing the sensitivity of tumor tissue to the radiotherapeutics. The ultimate goal of this study is to validate PARP1 targeted shuttles for Auger emitters in mouse models of glioblastoma. For this application, an interdisciplinary team of experts has been brought together to aid in the development of this technology. The research team will include Dr. Thomas Reiner (Radiochemistry and Probe Development), Dr. Wolfgang Weber (Nuclear Therapy), Dr. Ronald Blasberg (Neurology) and Dr. John Humm (Medical Physics). Together, the investigators form an ideal team to pursue this novel research avenue, bringing together expertise from a wide variety of disciplines. If successful, the generated data will form the foundation for a future clinical trial at MSK, directly impacting patient care and treatment of glioblastoma.